This invention relates to novel pyridazin-3-one derivatives, which have excellent inhibitory activity against interleukin-1xcex2 production and are useful for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases and the like, and also to medicines containing them as effective ingredients.
In many diseases, for example, rheumatism, arthritis, osteoporosis, inflammatory colitis, immune deficiency syndrome, ichorrhemia, hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson""s disease, Alzheimer""s disease, leukemia and the like, stimulation of interleukin-1xcex2 production, an inflammatory cytokine, is observed. This interleukin-1xcex2 serves to induce synthesis of an enzyme which is considered to take part in inflammation like collagenase and PLA2 and, when intra-articularly injected to animals, causes multi-articular destruction highly resembling rheumatoid arthritis. In the normal living body, on the other hand, interleukin-1xcex2 is controlled in activity by interleukin-1 receptor, soluble interleukin-1 receptor and interleukin-1 receptor antagonist.
From research conducted making use of recombinants of these bioactivity-inhibiting substances, anti-interleukin-1xcex2 antibodies and anti-receptor antibodies against various disease models, interleukin-1xcex2 has been found to play an important role in the body, leading to an increasing potential of substances having interleukin-1xcex2 inhibitory activity as therapeutics for such diseases.
For example, immunosuppressors and steroids which are used for the treatment of rheumatism out of such many diseases have been reported to inhibit the production of interleukin-1xcex2. Even among medicaments currently under development, KE298, a benzoylpropionic acid derivative [The Japanese Society of Inflammation (11th), 1990], for example, has been reported to,have inhibitory activity against interleukin-1xcex2 production although it is an immunoregulator. Inhibitory activity against interleukin-1xcex2 production is also observed on a group of compounds which are called xe2x80x9cCOX-2 selective inhibitorsxe2x80x9d, for example, nimesulide as a phenoxysulfonanilide derivative (DE 2333643), T-614 as a phenoxybenzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap (hydroxyindole derivative) as a dual inhibitor (COX-1/5-LO).
For all of these compounds, however, interleukin-1xcex2 production inhibitory activity is not their primary action so that their inhibitory activity against interleukin-1xcex2 production is lower than their primary action.
In recent years, increasingly active synthesis research is under way with a focus placed on inhibitory activity against interleukin-1xcex2 production. Production inhibitors can be classified into a group of compounds which inhibit the transfer process of an inflammatory signal to a cell nucleus and another group of compounds which inhibit an enzyme ICE that functions in the processing of a precursor of interleukin-1xcex2. Known examples of compounds presumed to have the former action include SB203580 [Japanese Language Laid-Open (Kokai) Publication (PCT) No. HEI 7-503017], FR167653 (Eur. J. Pharm., 327, 169-175, 1997), E-5090 (EP 376288), CGP47969A (Gastroenterology, 109, 812-828, 1995), hydroxyindole derivatives (Eur. J. Med. Chem. 31, 187-198, 1996), and triarylpyrrole derivatives (WO 97/05878), while known examples of compounds presumed to have the latter action include VE-13,045 which is a peptide compound (Cytokine, 8(5), 377-386, 1996).
None of these compounds can however exhibit sufficient inhibitory activity against interleukin-1xcex2 production.
On the other hand, it is known that a variety of 5,6-diphenylpyridazine derivatives have analgesic and anti-inflammatory action (Eur. J. Med. Chem., 14, 53-60, 1979). Absolutely nothing has however been known with respect to inhibitory activity of these 5,6-diphenylpyridazine derivatives against interleukin-1xcex2 production.
Accordingly, an object of the present invention is to provide a compound having excellent inhibitory activity against interleukin-1xcex2 production and also a medicine containing it as an effective ingredient.
Under such circumstances, the present inventors have proceeded with an extensive investigation. As a result, it has been found that pyridazin-3-one derivatives represented by the below-described formula (1) have excellent inhibitory activity against interleukin-1xcex2 production and are useful as medicines for the prevention and treatment of immune system diseases, inflammatory diseases and ischemic diseases, leading to the completion of the present invention.
Namely, the present invention provides a pyridazin-3-one derivative represented by the following formula (1): 
wherein Ar1 represents a substituted or unsubstituted aromatic group, Ar2 represents a phenyl group having a substituent at least at the 4-position thereof, R1 represents a linear or branched alkyl group, an alkyl group having a cyclic structure, a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenyl(lower alkyl) group, and R2 represents a cyano group, a carboxyl group, a (lower alkoxy)carbonyl group, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted carbamoyl group; or a salt thereof.
The present invention also provides a medicine comprising the pyridazin-3-one derivative (1) or the salt thereof as an effective ingredient.
Further, the present invention also provides an inhibitor of interleukin-1xcex2 production comprising the pyridazin-3-one derivative (1) or the salt thereof as an effective ingredient.
Furthermore, the present invention also provides a pharmaceutical composition comprising the pyridazin-3-one derivative (1) or the salt thereof and a pharmaceutically acceptable carrier.
Moreover, the present invention also provides use of the pyridazin-3-one derivative (1) or the salt thereof as a medicine.
In addition, the present invention also provides a method for treating a disease caused by stimulation of interleukin-1xcex2 production, which comprises administering the pyridazin-3-one derivative (1) or the salt thereof.
The pyridazin-3-one derivative according to the present invention is represented by the formula (1).
In the formula (1), examples of the aromatic group represented by Ar1 can include all aromatic hydrocarbon groups and heterocyclic aromatic groups, such as phenyl, naphthyl, pyridyl and quinolyl groups, with a phenyl group being particularly preferred. Illustrative of one or more substituents which the aromatic group may have are halogen atoms, lower alkoxy group,s lower alkylthio groups, lower alkylsulfinyl groups, and lower alkylsulfonyl groups. Examples of the halogen atoms can include fluorine, chlorine, bromine and iodine atoms. Examples of the lower alkyl moieties in the lower alkoxy, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl groups can include linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl groups. Among these substituents, lower alkoxy groups are preferred with a methoxy group being particularly preferred.
Illustrative of the substituent which the substituted phenyl group represented by Ar2 has at the 4-position thereof are lower alkoxy, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl groups. More specifically, groups similar to those exemplified above in connection with Ar1 can be mentioned, with lower alkoxy groups, especially a methoxy group being preferred. Further, the substituted phenyl group may be substituted at other position or positions by halogen atoms, lower alkoxy groups or the like. Examples of these halogen atoms and lower alkoxy groups can be similar to those exemplified above in connection with Ar1 can be mentioned.
Illustrative of the linear or branched alkyl group represented by R1 are those having 2 to 11 carbon atoms, for examples, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl and heptyl groups. Illustrative of the alkyl groups having cyclic structures are cycloalkyl groups having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups; and lower alkyl groups, such as methyl and ethyl groups, with such cycloalkyl groups substituted thereon. Examples of substituent groups on the substituted phenyl or phenyl(lower alkyl) group represented by R1 can include halogen atoms, lower alkyl groups, and lower alkoxy groups. Examples of these halogen atoms, lower alkyl groups and lower alkoxy groups can be similar to those exemplified above in connection with Ar1.
Examples of substituents on the substituted lower alkyl group represented by R2 can include halogen atoms, hydroxy groups, and substituted or unsubstituted phthalimido groups. Illustrative of substituents on the phthalimide groups are halogen atoms, nitro groups, lower alkoxy groups, and amino groups which may contain, as substituents, lower alkyl groups, lower alkylsulfonyl groups or lower alkylcarbonyl groups. Illustrative of the substituent or substituents on the substituted carbamoyl group represented by R2 are lower alkyl groups, aromatic groups, and lower alkyl groups substituted by aromatic groups. Illustrative of the lower alkyl moiety or moieties of the substituted lower alkyl or lower alkoxycarbonyl group represented by R2, the halogen atom or atoms as substituent or substituents of the substituted lower alkyl or lower alkoxy carbonyl group, the lower alkyl moieties of the lower alkyl, lower alkoxy, lower alkylsulfonyl, lower alkylcarbonyl and aromatic-group-substituted lower alkyl group, and the aromatic moieties of the aromatic group and aromatic-group-substituted lower alkyl group can be similar to those exemplified above in connection with Ar1. As the aromatic group, a phenyl or pyridyl group is particularly preferred.
Preferred specific examples of the pyridazin-3-one derivative (1) according to the present invention can include 5,6-bis(4-methoxyphenyl)-4-carbamoyl-2-cyclopropylmethyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-4-cyano-2-ethyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopropylmethyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopentylmethyl-2H-pyridazin-3-one, 2-benzyl-5,6-bis(4-methoxyphenyl)-4-ethoxycarbonyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-4-ethoxycarbonyl-2-isopropyl-2H-pyridazin-3-one, and 5,6-bis(4-methoxyphenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one.
Illustrative of the salts of the pyridazin-3-one derivative (1), said salt also pertaining to the present invention, are the hydrochloride, nitrate, hydrobromide, acetate, sulfate, p-toluenesulfonate, methanesulfonate, fumarate, succinate, lactate, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, methylammonium salt, dimethylammonium salt, and trimethylammonium. Further, the pyridazin-3-one derivative (1) or the salt thereof according to the present invention may exist in the form of a keto-enol tautomer and solvates. Such tautomer and solvates should also be encompassed by the present invention.
No particular limitation is imposed on a process for the preparation of the pyridazin-3-one (1) or the salt thereof according to the present invention, and a variety of processes, which have conventionally been used for the synthesis of pyridazine derivatives, and their modifications can be used. The pyridazin-3-one derivative (1) according to the present invention can be prepared, for example, by the following reaction scheme. 
wherein Ar1, Ar2, R1 and R2 have the same meanings, R3 and R4 may be the same or different and each independently represents a hydrogen atom, a lower alkyl group, an aromatic group or an aromatic-group-substituted lower alkyl group, X represents a halogen atom, R5 and R6 may be the same or different and each independently represent a hydrogen atom, a halogen atom, a nitro group, a lower alkoxy group, or an amino group which may have, as substituent or substituents, one or two of lower alkyl groups, lower alkylcarbonyl groups and lower alkylsulfonyl groups, and R7 represents a lower alkyl group.
The starting materials, i.e., the compounds represented by the formula (2) and (3), respectively, can be prepared by known processes (J. Med. Chem., 23, 1398-1405, 1980; Eur. J. Med. Chem., 14, 53-60, 1979).
This cyano-substituted pyridazin-3-one derivative can be prepared by reacting a compound, which is represented by R1xe2x80x94Y in which R1 has the same meaning as defined above and Y represents a halogen atom or a reactive esterified hydroxyl group, with a compound represented by the formula (2) in the presence of a base in a solvent.
Examples of the base usable in the reaction can include inorganic bases such as potassium carbonate and sodium carbonate and organic bases such as metal alkoxides. Usable examples of the solvent can include N,N-dimethylformamide, dimethylsulfoxide, acetone and methyl ethyl ketone. The reaction may be conducted preferably at 20 to 150xc2x0 C. for 1 to 20 hours, notably at 50 to 130xc2x0 C. for 2 to 10 hours.
This carbamoyl-substituted pyridazin-3-one derivative (1b) can be prepared by reacting a base, such as caustic soda or caustic potash, with the compound (1a) in a solvent.
This ethoxycarbonyl-substituted pyridazin-3-one derivative (1c) can be prepared by reacting R1xe2x80x94Y, which was also used in (A), with the compound represented by the formula (3) in the presence of a base in a solvent.
Examples of the base usable in the reaction can include inorganic bases such as potassium carbonate and sodium carbonate and organic bases such as metal alkoxides. Usable examples of the solvent can include N,N-dimethylformamide, dimethylsulfoxide, acetone and methyl ethyl ketone. The reaction may be conducted preferably at 20 to 150xc2x0 C. for 1 to 20 hours, notably at 50 to 130xc2x0 C. for 2 to 10 hours.
This carboxyl-substituted pyridazin-3-one derivative (1d) can be prepared by hydrolyzing the compound (1c) in the presence of a base, such as caustic soda or caustic potash, in a solvent in a manner known per se in the art.
This substituted-carbamoyl-substituted pyridazin-3-one derivative (1e) can be prepared by converting the compound (1d) at the carboxyl group thereof into a reactive derivative and then reacting it with a corresponding amine R3R4NH in which R3 and R4 have the same meanings as defined above.
Examples of the reactive derivative at the carboxyl group can include acid halides and mixed acid anhydrides. Conversion into such an acid halide can be effected with oxalyl chloride, thionyl chloride, thionyl bromide or the like. Conversion into such a mixed acid anhydride, on the other hand, can be effected with acetic anhydride, pivalic anhydride, methanesulfonic anhydride, p-toluenesulfonyl chloride or the like. The synthesis reaction of the reactive derivative may be conducted preferably in the presence or absence of a base at xe2x88x9210 to 150xc2x0 C. for 1 to 20 hours, especially at 0 to 130xc2x0 C. for 1 to 10 hours in a solvent, for example, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, pyridine, chloroform, methylene chloride, toluene or benzene.
This hydroxymethyl-substituted pyridazin-3-one derivative (1f) can be prepared by reacting an alkyl halocarbonate compound, such as ethyl chlorocarbonate, with the compound (1d) in the presence of a base such as triethylamine in a solvent to form a mixed acid anhydride and then reacting sodium borohydride with the mixed acid anhydride.
Usable examples of the solvent can include tetrahydrofuran, dioxane, diethyl ether, and ethyl acetate. The reaction may be conducted preferably at xe2x88x9220 to 50xc2x0 C. for 0.5 to 10 hours, notably at 0 to 30xc2x0 C. for 0.5 to 3 hours.
This halogenated-methyl-substituted pyridazin-3-one derivative (1g) in which X is a chlorine atom: or bromine atom can be prepared by reacting a halogenating agent, such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride or phosphorus tribromide, with the compound (1f) in a solvent. Further, the halogenated-methyl-substituted pyridazin-3-one derivative (1g) in which X is an iodine atom can be prepared by reacting sodium iodide, potassium iodide or the like with the above compound in a solvent.
Usable examples of the solvent for the halogenation (chlorination, bromination) can include benzene, toluene, tetrahydrofuran, dioxane, diethyl ether, ethyl acetate, and chloroform. The reaction may be conducted preferably at 20 to 130xc2x0 C. for 0.5 to 5 hours, especially at 30 to 100xc2x0 C. for 1 to 3 hours. In the preparation of the compound (1g) in which X is an iodine atom, acetone, methyl ethyl ketone, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, chloroform or the like can be used as the solvent. The reaction may be conducted preferably at 40 to 150xc2x0 C. for 0.5 to 10 hours, notably at 50 to 120xc2x0 C. for 1 to 5 hours.
This compound (1h) which has a (substituted) phthalimidomethyl group at the 4-position can be prepared by reacting potassium phthalimide or substituted potassium phthalimide with the compound (1g) in a solvent.
Usable examples of the solvent can include N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, benzene, and toluene. The reaction may be conducted preferably at 50 to 150xc2x0 C. for 0.5 to 5 hours, notably at 70 to 120xc2x0 C. for 1 to 3 hours.
This (lower alkoxy)carbonyl-substituted pyridazin-3-one derivative (1i) can be prepared by reacting a lower alcohol R7xe2x80x94OH, in which R7 has the same meaning as defined above, with the reactive derivative of the compound (1d) at the carboxyl thereof, which was used in the preparation of the compound (1e), in the presence or absence of a base in a solvent such as tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, pyridine, chloroform, methylene chloride, toluene or benzene. As an alternative process, it can also be prepared by a usual ester preparation process, namely, by reacting the lower alcohol R7xe2x80x94OH with the compound (1d) in the presence of an acid catalyst in a solvent.
The intermediates and target compounds obtained in the above-described individual reactions can be separated and purified by purification methods commonly employed in organic synthesis chemistry, for example, by subjecting them to filtration, extraction, washing, drying, concentration, recrystallization, various chromatographic treatment, and the like. The intermediates may be provided for the next reactions without purifying them specifically. Further, they may also be obtained as solvates of solvents such as reaction solvents or recrystallization solvents, especially as hydrates.
The pyridazin-3-one derivatives (1) and their salts according to the present invention, which are available as described above, have excellent inhibitory activity against interleukin-1xcex2 production, and are useful as preventives or therapeutics for immune system diseases, inflammatory diseases, ischemic diseases, osteoporosis, ichorrhemia, rheumatism, arthritis and inflammatory colitis.
Medicines according to the present invention contain the pyridazin-3-one derivatives (1) or their salts as effective ingredients. Using them alone or together with pharmacologically-acceptable carriers such as solubilizers, excipients, binders or extenders, they can be formed into pharmaceutical preparation forms such as tablets, capsules, granules, powders, injections and suppositories. These pharmaceutical preparations can be produced by known methods. For example oral preparations can be produced by suitably formulating the pyridazin-3-one derivatives (1) or their salts in combination with solubilizers such as tragacanth gum, gum arabic, sucrose esters, lecithin, olive oil, soybean oil and PEG400; excipients such as starch, mannitol and lactose; binders such as carboxymethylcellulose sodium and hydroxypropylcellulose; disintegrators such as crystalline cellulose and carboxymethylcellulose calcium; lubricants such as talc and magnesium stearate; anticaking agents such as light anhydrous silicic acid.
The dosage of each medicine according to the present invention varies depending on the body weight, age, sex, conditions and the like. In general, however, it is preferred to orally or parenterally administer to an adult the medicine in an amount of about 0.01 to 1,000 mg, preferably 0.1 to 100 mg in terms of the compound represented by the formula (1) per day at once or in several portions.